Good afternoon. So these are my disclosures for this talk. So from an outline standpoint, we'll start with reviewing the etiologies of AKI and their prognostic value in decomposite cirrhosis slash ACLF. And then we'll talk about something that's important is the evolution of the diagnostic criteria with respect to HRS, which has made a real difference in the past few years as far as prognosis and therapy. And then we'll go into the current guidelines for the diagnostic evaluation of HRS AKI in decomposite cirrhosis. One thing I'd like to highlight when we get to that part is the sort of the universal acceptance now between the Europeans and the Americans regarding thinking similarly about the treatment guidelines. And then we'll get into the role of biomarkers, and specifically there is interesting data regarding urinary engel. So we'll talk about that in this context. And then finally, I want to finish up with the, as you think about AKI in cirrhosis, I think the other factor we need to think about is the implications of CKD that the patient may have before they come into the ICU that may affect your strategies as far as managing their AKI. So let's talk about etiologies of AKI and their prognostic value. So when you think about etiologies of AKI, similar to what we do in the ICU, you're looking at the differential diagnosis of prenatal azothemia, HRS, ATN, and then just some of the other things we need to think about in the context of ACLF, especially a sick ACLF patient is intra-abdominal hypertension from 10 societies that can be a factor for AKI. And then rarely in the severely jaundiced patient, mild castor nephropathy can also contribute to AKI. So as all critical care providers here, we're thinking broadly as far as the differential diagnosis. And so that's an important take-home message here is the AKI in ACLF can be multifactorial. So as we think about sort of teasing out the HRS component, there may be a multipronged effort as far as treating these patients with AKI. And also the multifactorial nature of this does create challenges as far as diagnostic and therapeutic management. All right, now let's talk about prevalence and causes of AKI and cirrhosis. What's the data there? So this is a list of publications over the years with varying sample sizes. And as you can see, they've been teased out into AKI prevalence and then the different potential ideologies, hypovolemia, i.e. prenatal azotemia, ATN, HRS. And as you can see, the percentages have varied over the years as you look at these different studies. And I think the variation in the numbers is influenced by what the definition of AKI that was used in that particular study and the specific patient population that was studied. And then to add on to this, I think the revised definition of HRS-AKI based on the KDGO guidelines that we'll talk about will increase the diagnostic rate as you're defining HRS-AKI differently compared to the previous definition. And we'll elaborate on this a bit more. So let's talk about prognostic importance of AKI. And I think Dean has already alluded to this in his introduction. And just a couple of studies I want to bring to your attention. This is from 2011 that looked at the different ideologies of AKI in a cirrhotic population. And as you can see, compared to other ideologies, HRS had a worse mortality. And HRS in this series was independently associated with a higher 90-day mortality compared to hypervolemia, parenchymal nephropathy, and the other category is infection. Similar data, more but more recent, coming out of Boston, a single-center study. Again, looking at survival curves, you can see that compared to prenal azotemia, there's definitely a worse prognosis with respect to HRS-AKI. Interestingly, in this study, ATN and the HRS curve superimpose, a sort of similar prognostic implications. So all that to say that I think all these studies over the years highlight the fact that there is increased mortality associated with the HRS phenotype of AKI, and therefore it becomes very important to have accurate diagnosis that is early, and also which can then lead to early therapy that Dr. Olson will talk about in much detail. So let's switch gears and talk about the evolution of diagnostic criteria in HRS, and luckily we've achieved this. It took us a while, but I think we got there. Just to give you an idea of, we were living in the dark ages in the hepatology world, and just on the left is the sort of the old name, HRS Type 1, and just to draw your attention, we were waiting for a creatinine of 2.5 in a cirrhotic population before we invoked a diagnosis of HRS, which was unfortunate. So having said that, we have now evolved to redefining HRS AKI, similar to the KDGO guidelines. We're looking for an increase in serum creatinine of as little as 0.3 over 48 hours, which becomes clinically important, as you all know, in general intensive care, and also an increase in serum creatinine of 1.5 times from baseline. So there's definitely been a shift in the diagnostic criteria, which has enabled us to diagnose this more accurately, earlier, and also have the opportunity to administer therapy in a more effective manner. So I think there's an important shift. A lot of you may be familiar with this change, but I think I just want to recap on how we've redefined HRS AKI in the literature. So moving on to staging of HRS AKI, again, we have extrapolated from what we do in general critical care. But just to sort of recap on this, stage 1 is defined as an increase in serum creatinine of 0.3 within 48 hours, or an increase in the serum creatinine between 1.5 to 2 from baseline. The other thing I want to draw your attention to is the distinction between stage 1a and 1b, and that is defined as stage 1b is defined as a creatinine greater than 1.5. And this will become important when we look at the prognostic implications of this distinction. And then just to finish up, stage 2 is basically when you double your creatinine. And that will become important, as Dr. Olson will talk about, as far as that may be your trigger to think about vasoconstrictor therapy. And then stage 3 is basically a worsening of the spectrum. And then this is at least a threefold increase, or you are getting to dialysis. Interestingly, and hopefully this will evolve over time as well, when we first made these criteria in the liver world, we did not incorporate urine output in oliguria, which I hope there's an opportunity to rectify in the next version of the guidelines. And there is data suggesting, and Dr. Olson will elaborate on this as well, that when you incorporate urine output in oliguria into the diagnostic criteria, like we do for general critical care, that increases the utility of the prognostic model. So but at this stage, strictly speaking, we have not included urine output in the diagnostic criteria. So now let's talk about prognostic utility. How do these stages translate to worsening mortality? And to just draw your attention to this, and I want to draw your attention to distinguishing stage 1a and 1b as well. As you can see, again, looking at the survival curves here, there is a significant difference between stage 1a AKI and stage 1b. So basically creatinine less than or equal to 1.5. And so that will have implications when you look at the algorithm with respect to diagnosis and therapy. And just to draw you, again, similar data, that when you look at hazard ratios and 90 percent mortality, it does make a difference when you're distinguishing stage 1a and stage 1b. And this is now being incorporated into both European and U.S. treatment guidelines. All right. So based on all of that, what is the current guidelines for the diagnostic evaluation of AKI, and specifically HRS AKI? So you're starting from the top, and you come into a creatinine greater than 1.3, and then you distinguish between stage 1a, where your serum creatinine is less than 1.5, or you've exceeded that and you've gone to stage 1b, stage 2, or stage 3. So just walking down the left side of the algorithm, when you're stage 1a, it's close monitoring, eliminating all potentially nephrotoxic interventions, and then plasma volume expansion, even with crystalloid for that matter. And then you see if there's response to that initial therapy. If you worsen, then you will go into the right side of the diagram, and so just going and focusing here. If you have stage 1b, stage 2, or stage 3, here's where it becomes a trigger to give a sufficient volume challenge, defined in this protocol as albumin, one gram per kilogram for two days. And that's your strategy to distinguish potentially between prenal isothermia and true HRS AKI. And then you go down this algorithm, and this is where you will then rule out ATN with your usual algorithm of looking at a urine. And then if you still have refractory AKI, then you can invoke a diagnosis of HRS AKI, and then become a candidate for vasoconstrictive therapy with albumin that Dr. Olson will talk about shortly. All right, so just to sort of recap on this, I just want to highlight again the distinction between stage 1a and 1b, and then we'll also talk about the AGA guidelines, which is the gastroenterology guidelines, also invoke the potential utility of urinary biomarkers, in particular urinary NGAL that I'll show you some data on. So moving on to biomarkers, and I just want to draw your attention to this publication from last year, which I think was a very interesting paper looking at the utility of urinary NGAL in patients with cirrhosis and AKI, and walking through these different graphs. On the left is looking at urinary NGAL for different etiologies, and you can see pre-renal azotemia and HRS AKI have relatively low NGAL levels, and the ATN phenotype has much higher NGAL levels, and this is mixed AKI. The second thing that was interesting in this paper is this middle diagram where, when you're looking at turlepressin responders, and you'll hear more about turlepressin from Dr. Olson, which is your vasoconstrictive therapy, you can see that the non-responders compared to the responders had higher levels of baseline urinary NGAL, so you can use urinary NGAL to predict response to turlepressin therapy. And then finally, something that's interesting is looking at response rate by absolute value. So the cutoff here, based on the modeling, was if you have, and this is for all turlepressin dosing, if you have a urinary NGAL less than 220, you have a higher chance of resolution of HRS AKI. So again, very interesting data that highlights the potential utility of urinary NGAL in the management of HRS AKI. Currently, to my knowledge, this is not widely available in the U.S., but something to stay tuned for. And then finally, I want to finish up with CKD and the implications of sort of CKD, and the AKI superimposed CKD, and how that can influence your management. Again, when you think about CKD in cirrhosis and the potential etiologies, the big-ticket item is NASH, is sort of a growing epidemic, and that comes with its baggage of diabetic nephropathy, hypertensive nephropathy, so a lot of our cirrhotic patients in that phenotype may have some underlying CKD. And then there's also a category of HRS CKD, which is not HRS AKI, but it's more subacute HRS physiology that can predispose that cirrhotic patient to CKD as well. And then just to finish up, other rarer etiologies in alcoholic and OIG and nephropathy, and then viral hepatitis, like hepatitis B or hepatitis C, can be a risk factor for MPGN. So as you think about this spectrum of potential CKD etiologies, and again, I want to highlight NASH, which is a big epidemic in the world, including the U.S., that definitely increases the risk of underlying CKD as you manage these patients for superimposed AKI. And so just to summarize this is that the presence of underlying CKD can further complicate the diagnostic evaluation of HRS AKI and have implications regarding timing of CRT and also consideration for combined liver-kidney transplant in select populations. So just to summarize some points, AKI and cirrhosis and ACLF can have multiple etiologies that can contribute simultaneously to renal dysfunction. Luckily, the definition of HRS AKI has evolved to incorporate AKI concepts from what we do in general critical care, thereby facilitating earlier diagnosis and earlier therapy. We spoke about revised clinical practice guidelines that hopefully will standardize management of HRS AKI. I shared with you the potential utility of Unary NGAL in particular as a biomarker in the management of HRS AKI. And finally, acknowledgement of the presence of underlying CKD in certain patients that can influence your management of AKI. Thanks for your attention. Thank you.

Acute Kidney Injury

Cirrhosis

Acute-on-chronic liver failure

Hepatorenal Syndrome

Chronic Kidney Disease